Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder characterized by a range of symptoms that include muscle weakness (myopathy), difficulty relaxing muscles (myotonia), progressive muscle wasting (atrophy), cataracts, cardiac defect, and insulin dependent diabetes, There is an urgent need to discover lead agents for treating DM1 because it affects about 1 in 8,000 people, yet it remains incurable with no direct therapeutic options.
DM1 results from a progressive expansion of the trinucleotide CTG repeat in the 3′-untranslated region of the dystrophia myotonia protein kinase (DMPK) gene on chromosome 19q13.3. The number of CTG repeats is less than 35 in healthy people, and ranges from 50 to thousands in DM1 patients. The molecular origin of DM1 was previously attributed to three possible mechanisms: (1) DMPK haloinsufficiency, (2) decreased expression of neighboring genes, including SIX5 and DMAHP, and (3) a gain-of-function for the expanded RNA transcript (rCUGexp). Recent studies have argued against the first two hypotheses, leaving the third mechanism as the favored one for therapeutic intervention.
The gain-of-function model involves expanded rCUG repeats forming stable stem-loop structures with U-U mismatches flanked by G-C and C-G base pairs, and sequestering important proteins. Key among these proteins is the muscleblind-like (MBNL) protein, a key alternative splicing regulator. The loss of MBNL1 results in abnormal alternative splicing of more than 100 pre-mRNAs, including cardiac troponin T (cTNT), insulin receptor (IR) and chloride channel 1 (CIC-1). Supporting the toxic RNA model is the finding that overexpression of MBNL1 protein in the skeletal muscle of a DM1 mouse model relieved the myotonia and abnormal RNA splicing. The MBNL1-rCUGexp complex formation has emerged as a key therapeutic target for DM1. Because there are currently no effective therapies for DM1, there is an urgent need for a new compounds and methods for the study and treatment of the disease.